The present invention provides methods for diagnosing cancer, particularly metastatic cancer.
The increased number of cancer cases reported around the world is a major concern. There are currently only a few treatments available for specific types of cancer, and these provide no absolute guarantee of success. Most treatments rely on an approach that involves killing off rapidly growing cells in the hope that rapidly growing cancerous cells will succumb, either to the treatment, or at least be sufficiently reduced in numbers to allow the body's system to eliminate the remainder. Moreover, many of these treatments adversely effect non-malignant cells. Consequently, an appreciation of the severity of the condition must be made before beginning many therapies. In order to most effective, these treatments require not only an early detection of the malignancy, but an appreciation of the severity of the malignancy.
While different forms of cancer have different properties, one factor which many cancers share is that, in order to be fatal, they must metastasize. Until such time as metastasis occurs, a tumor, although it may be malignant, is confined to one area of the body. This may cause discomfort and/or pain, or even lead to more serious problems, but if it can be located, it may be surgically removed and, if done with adequate care, cause no further problems. However, once metastasis sets in, cancerous cells have invaded the body and while surgical resection may remove the parent tumor, this does not address other tumors. Only chemotherapy, or some particular form of targeting therapy, then stands any chance of success.
The process of tumor metastasis is a multistage event involving local invasion and destruction of intercellular matrix, intravasation into blood vessels, lymphatics or other channels of transport, survival in the circulation, extravasation out of the vessels in the secondary site and growth in the new location (Fidler, et al., Adv. Cancer Res. 28, 149-250 (1978), Liotta, et al., Cancer Treatment Res. 40, 223-238 (1988), Nicolson, Biochim. Biophy. Acta 948, 175-224 (1988) and Zetter, N. Eng. J. Med. 322, 605-612 (1990)). Success in establishing metastatic deposits requires tumor cells to be able to accomplish these steps sequentially. Common to many steps of the metastatic process is a requirement for motility. The enhanced movement of malignant tumor cells is a major contributor to the progression of the disease toward metastasis. Increased cell motility has been associated with enhanced metastatic potential in animal as well as human tumors (Hosaka, et al., Gann 69, 273-276 (1978) and Haemmerlin, et al., Int. J. Cancer 27, 603-610 (1981)).
Tumor angiogenesis is essential for both primary tumor expansion and metastatic tumor spread, and angiogenesis itself requires ECM degradation (Blood et al., Biochim. Biophys. Acta 1032:89-118 (1990)). Thus, malignancy is a systemic disease in which interactions between the neoplastic cells and their environment play a crucial role during evolution of the pathological process (Fidler, I. J., Cancer Metastasis Rev. 5:29-49 (1986)).
Identifying the alterations in gene expression which are associated with malignant tumors, including those involved in tumor progression, is clearly a prerequisite not only for a full understanding of cancer, but also to develop new rational therapies against cancer.
A further problem arises, in that the genes characteristic of cancerous cells are very often host genes being abnormally expressed. It is quite often the case that a particular protein marker for a given cancer while expressed in high levels in connection with that cancer is also expressed elsewhere throughout the body, albeit at reduced levels.
Prostatic carcinoma is the most prevalent form of cancer in males and the second leading cause of cancer death among older males (Boring, et al., Cancer J. Clinicians, 7-26 (1994)). Clinically, radical prostatectomy offers a patient with locally contained disease an excellent chance for cure. Unfortunately, if diagnosed after metastases are established, prostatic cancer is a fatal disease for which there is no effective treatment to significantly increase survival. Recent advances in prostatic cancer diagnosis has allowed the earlier detection of human prostate cancer by use of the PSA test (Catalona, et al., J. Urol, 151, 1283-1290 (1994)). Unfortunately, this early detection has not been accompanied by an improvement in determining which tumors may progress to the metastatic stage (Cookson, et al., J. Urology 154, 1070-1073 (1995) and Aspinall, et al., J. Urology 154, 622-628 (1995)). Since many individuals having prostate cancer are not adversely effected by the cancer, considerable controversy has arisen as to the use of such tests. Thus, methods for early detection and early appreciation of the potential for or of the severity of the cancer, that can be taken into account in treatment of, for example, metastatic disease are desirable.
Bao and Zetter reported in an abstract presented at the American Association for Cancer Research annual meeting (Mar. 18-22, 1995) the differential expression of a novel mRNA expressed in high-metastatic rat tumor cell lines, but not in a low metastatic variant. cDNA was isolated and was reported to encode a protein with 68% identity to the rat thymosin .beta.4. However, the nucleotide sequence and the deduced amino acid sequence were not reported.